Cancer is the leading cause of death, second only to heart disease, of both men and women. In the fight against cancer, numerous techniques have been developed and are the subject of current research, directed to understanding the nature and cause of the disease, and to provide techniques for control or cure thereof.
Three major families of antitumor agents are known. Each of the families of agents is associated with a recognized mechanism of action. First, antitumor agents may be alkylating agents, which generally bind in a covalent manner with DNA to form bifunctional lesions. The bifunctional lesions involve adjacent or nearby bases of the same strand, or alternatively, involve bases on opposite strands forming interstrand crosslinks. Second, antitumor agents may be antimetabolites, which generally inhibit enzymes involved in the synthesis or assembly of DNA. Alternatively, an antimetabolite may serve as a fraudulent or analog substrate of DNA processes. Third, antitumor agents may be antibiotics, which work by intercalating into the DNA helix or introducing strand breaks into DNA.
Thousands of potential anticancer agents have been evaluated. Essentially, all effective agents (of which very few have been found) appear to work by one of the above-mentioned mechanisms.
Drug targeting is a potentially attractive new approach to killing malignant cells, which leaves normal tissue unharmed. A decisive breakthrough in drug targeting was the advent of hybridoma technology, making monoclonal antibodies (MoAb) available in limitless supply. To construct reagents with selectivity for certain populations of tumor cells, MoAbs or other cell targeting proteins are linked to bioactive agents to form immunoconjugates which combine the selectivity of the carrier moiety with the potency of the bioactive moiety. The choice of monoclonal antibody is based on the surface antigen profile of a malignant cell as determined by analysis of clonogenic blasts.
For the past decade, immunoconjugates have been under investigation for the treatment of various cancers, and more recently for the treatment of immunological disorders such as rheumatoid arthritis and acquired immune deficiency syndrome (AIDS). Although these agents have shown some potential to provide safe and effective therapy for human disease, many difficulties remain. Ideally, consistently locatable and reliable markers on target cells would permit the binding portion of immunoconjugates to completely avoid non-target tissue. In reality, cross-reactivity with antigens expressed by vital life-maintaining organs often gives rise to unacceptable complications in in vivo applications. There is also the potential that patients will demonstrate immune responses to the separate components of the immunoconjugates even though they may already be immunosuppressed by the course of their disease. Moreover, the cytotoxicity obtained in in vitro studies may be limited in clinical application due to a lack of potency in doses that can be tolerated by the patient. Finally, solid tumors are difficult to penetrate thoroughly and in hematologic malignancies, residual disease can cause relapse despite easier access to target cells in leukemias and lymphomas.
Thus, there are serious and recurring problems with immunoconjugate therapy. Therefore, there is continuing need for improved agents and methods of their use to target and inhibit or eliminate cell populations associated with various pathologies.